The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase

Abstract

The DNA methyltransferases, Dnmts, are the enzymes responsible for methylating DNA in mammals, which leads to gene silencing. Repression by DNA methylation is mediated partly by recruitment of the methyl-CpG-binding protein MeCP2. Recently, MeCP2 was shown to associate and facilitate histone methylation at Lys9 of H3, which is a key epigenetic modi®cation involved in gene silencing. Here, we show that endogenous Dnmt3a associates primarily with histone H3-K9 methyltransferase activity as well as, to a lesser extent, with H3-K4 enzymatic activity. The association with enzymatic activity is mediated by the conserved PHD-like motif of Dnmt3a. The H3-K9 histone methyltransferase that binds Dnmt3a is likely the H3-K9 speci®c SUV39H1 enzyme since we ®nd that it interacts both in vitro and in vivo with Dnmt3a, using its PHD-like motif. We ®nd that SUV39H1 also binds to Dnmt1 and, consistent with these interactions, SUV39H1 can purify DNA methyltransferase activity from nuclear extracts. In addition, we show that HP1b, a SUV39H1-interacting partner, binds directly to Dnmt1 and Dnmt3a and that native HP1b associates with DNA methyltransferase activity. Our data show a direct connection between the enzymes responsible for DNA methylation and histone methylation. These results further substantiate the notion of a self-reinforcing repressive chromatin state through the interplay between these two global epigenetic modi®cations.

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

“…The results suggest that MeCP2 may play a role in epigenetic silencing of the LIF gene in untransformed MCF-10A cells via binding to the hypermethylated DNA within the promoter region. We next examined histone methylation patterns within the LIF promoter to understand the influence of DNA methylation on histone methylation and vice versa (Fuks et al, 2003a;Vaissiere et al, 2008). Our results were similar to the data of MeCP2 occupancy within the LIF promoter.…”

“…DNA methylation has been recently linked to methylation of Lys9 of histone H3, which is a histone mark for transcriptional repression. Histone methylation can direct DNA methylation (Fuks et al, 2003a;2003b).…”

Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b

“…This cooperativity or redundancy is most easily explained by interchangeability between the two proteins in epigenetic repressor complexes present in human cancer cells. In support of this idea, both DNMT1 and DNMT3b are known to bind various epigenetic repressors, including HDACs, histone methyltransferases, and Polycomb group proteins (Bird and Wolffe, 1999;Fuks et al, 2003;Vire et al, 2006). Furthermore, both DNMT1 and DNMT3b are often overexpressed in human cancer cells (Robertson et al, 1999).…”

Gradual development of a genome‐wide H3‐K9 trimethylation pattern in paternally derived pig pronucleus

“…has been observed in diverse biological systems (Tamaru and Selker, 2001;Fahrner et al, 2002;Jackson et al, 2002;Fuks et al, 2003;Lehnertz et al, 2003;Tariq et al, 2003;Freitag et al, 2004). Therefore, the different H3-m 3 K9 states in the two species prompted us to investigate DNA methylation states in sperm-derived chromatins.…”